disubstituted



Patented Aug. 11, 1959 11,17 DISUBSTITUTED 3 KETO-A -5 ANDROSTATRIENES David H. Gould, Leonia, Hershel L. Herzog, Mountain View, and Emanuel B. Hershberg, West Orange, N..l., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Application January 25, 1957 Serial No. 636,229

13 Claims. (Cl. 260-3973) This invention relates to a new group of steroid compounds which possess valuable therapeutic properties, and to the methods for preparing same. More particularly, this invention relates to 3-keto-1,4,6-androstatrienes and their 9a-fluoro analogues which possess at the l7-position a keto or hydroxyl group.

The new compounds are useful anabolic agents in the treatment of cachexia, and in regenerating tissue loss due to burns, or protein loss following an operation. These compounds cause a beneficial euphoria. In addition, they are useful as pituitary regulators. ent in the 9-position, not only are the above therapeutic activities greatly enhanced, but the compounds exhibit anti-inflammatory properties.

The compounds of our invention may be represented by the following formula: I

Acetic Anhydride When fluorine is preswherein X is a member of the group consisting of hydrogen and fluorine; Y is a member of the group consisting of and =0; and Z is'a member of, the group consisting of and n V H t CH3 The 17-keto androstatrienes of this invention may be prepared by the sodium bismuthate or chromic anhydride oxidation of a 3,20 diketo-1,4g6-pregnatriene.or its fluoro analogue whose preparations are described in copending patent application of Gould et al., Serial No. 513,901, filed June 7, 1955. The 17-keto group of these compounds may be selectively reduced to a B-hydroxy group by means of the microbiological activity of Saccharomyces cerevisiae. To prepare the new compounds wherein X=H and we prefer to employ the following sequence of reactions:

p-toluenesulfonic acid 0 OH I --CH:

OH I 1. CH MgI I B. Sphaerlcus 2. Acetic acin 0 sodium acetate III oAo 0A0 ---CH; 0A0 1 GAO I I 'lN-bromosuccinlmide v I Collidine I l I OH I 'F.-dehydrogenahs i I VIII In the foregoing sequence, the 3-keto group of 4-androstene-11B-ol-3,17-dion'e (I) is selectively protected such as by forming the eneamine, II. Reaction of II with methyl magnesium halide in a conventional Grignard reaction followed by hydrolysis yields 17a-methyl-4- androstene 1113,1718 .,-,diol 3 one (III). A-ring dehydrogenation whereby III is converted to the 1,4-diene, IV, is conveniently elfected, microbiologically by means of B. Sphaericus according/to. the-procedure described in copending application of Charney et al., Serial No. 570,210, filed March 8,, 1956. The diacetate, V, is formed in the usual manner an-dis brominated with an agent such as N-bromosuccinimide to form 6-bromo-l7umethyl 1,4 androstadiene 11 8,1713 diol 3 one 11,17-diacetate (VI). Dehydrobromination of this compound may be effected by refluxing with a tertiary amine such as collidine to obtain the 1,4,6-androstatriene 11,17- diacetate (VII). chemically or preferably microbiologicall'y'b'y means pr the microorganism Flavobacterium dehydrogenans var I hydrolylicum according to the procedure described in copending application of-Charney, Serial No. 458,661, filed September 27, 1954,-now,abando ned, yielding.1-7arm ethyl- 1,4,6-androstatriene-1 15,17,3-diol-3-one (VIII).

Alternatively, the triene VIII may bepreparedjaccording to the following reaction scheme:

OAC

III

17a methyl 4 androstene 115,175 diol 3 one (HI) is acetylated with acetic anhydride inthe presence of a strong acid such as-p-toluenesulfonic acid to yield the invention, i.e.

This, in turn, isqbromin- I methane snltony] chloride e ia etate, Y maytbes penifi 7 one ---oH,

H Acetic Anhydridc I N-bromosuccim'mide MM 0: p-toluene sulfonlc acid F. dehydroqemms r drobromination is effected by refluxing compound X with a tertiary base such as collidine, yielding 17a-methyl-4,6- androstadiene 11 9,1719 diol 3 one 11,17 diacetate (XI). Hydrolysis of XI by means of Flavobacterium dehydrogenans var. hydrolyticum gives the diol, Xil. A -dehydrogenation of XII by Bacillus sphaericus yields the triene VIII.

The ll-keto .cornpound, 17a-methyl-1,4,6 androstatriene-17fi-ol-3,1l-dione, may-be prepared by any of the following methods:

(.1) Oxidation of compounds. VIII.-.with chromic anhydride,

(2) Employing the sequence of reactions from compounds I and "VII, using 4-androstene.-3,l1,17-trione as the starting material. flInpthis .ease, in view of the stability of the 17fl-hydroxyl group in thepresence of a 17amethyl group, it is not necessary to prepare a protective acetate of the 17fl-hydroxy1 compound analogous to IV, i.e. 17a-methyl-1,4-androstadiene-17,3-01-3,ll-dione.

('3) Employing the same reactions as in method 2, but introducing the double bonds in ajdifferent sequence. For example, the ll-keto compound corresponding to III, i.e. 17ot1methyl-4-androstene-17fl ol3,1l-dione may first be brominated and subsequently dehydrobrominated to form the corresponding 4,6-androstadiene. This, in turn, may

on ----cH,

B. Sphaericus I VIII XII

finally be subjectedtodhe action of B. sphaericus to introduce the A bond, so as to form a compound of this 17a-methyl-1,4,6-androstatriene-175-01- l 3,11 dione.

Compounds of the general formula containing a methyl and a 9a-fluoro group are prepared as follows:

OH OH -CHa ---CH3 OH I l l N-bromoaeetamlde Potassium Acetate x111 XIV i en N-bromosuccinimlde 17a-methyl-1,4-androstadiene-1 1B,17 3-diol-3-or1e (IV) is dehydrated with an agent such as methane sulfonyl chloride to form the 1,4,9(11)-androstatriene (XIII) which, in turn, is hydroxy-brominated to the 9a-bromollfi-hydroxy-diene (XIV) with N-bromoacetamide or N- bromosuccinimide. A dehydrobromination with a base such as potassium acetate follows to form the 95,115- oxido compound (XV). Bromination (compound XVI) is effected through the use of an agent such as N-bromosuccinimide, followed by dehydrobromination by refluxing in a tertiary base such as lutidine to obtain 17amethyl-1,4,6-androstatriene-9fl, l 1 ,S-oxido-17i3-ol (XVII). The addition of hydrogen fluoride converts this product to a compound of this invention, 90t-fll10IO-170L-Inethy1- 1,4,6-androstatriene-11,8,17fi-diol-3-one (XVIII). When XVIII is oxidized in a conventional manner with chromic anhydride in acetic acid, the corresponding ll-keto compound of this invention (XIX) is obtained.

The intermediate XIII, is alternatively prepared by dehydrating 17oz methyl-4-androstene-1118,175-diol-3-one (III) with an agent such as methane sulfonyl chloride to form 170: methyl-4,9(11)-androstadiene-17,8-ol-3-one, which may then be subjected to the action of Bacillus sphaericus var. fusiformis to obtain 17u-methyl-1,4,9(11)- androstatriene-l75-ol-3-one (XIII).

The foregoing is more fully described in the following examples which are not to be construed as limiting the scope of this invention, but are given for illustrative purposes only.

EXAMPLE 1 1,4,6-androstatriene-l Idol-3,1 7-dione The requisite intermediate, 1,4,6-pregnatriene-115,17, 2l-triol-3,20-dione is prepared as described in copending patent application, Serial No. 513,901, filed on June 7, 1955, by David H. Gould and Hershel L. Herzog.

A sample of 0.5 g. of 1,4,6-pregnatriene-l1B,17a,2ltriol-3,20-dione is dissolved with warming in 50 ml. of acetic acid and 50 ml. of water is added. Sodium bismuthate (8 g.) is added and the mixture is stirred overnight at room temperature. The solid is filtered, washed with methylene chloride, then discarded. The filtrate is further diluted with water, extracted with methylene chloride and washed neutral with sodium bicarbonate solution. The dried solution is evaporated to a residue which is crystallized from acetone-hexane to yield the pure 1,4,6-androstatriene-11,6-ol-3,17-dione.

EXAMPLE 2 1,4,6-andrstatriene-3,11,17-tri0ne [The requisite intermediate, 1,4,6-pregnatriene-17a,21- diol-3,11,20-trione is prepared as described in copending OH OH ca: A ---cH Q o 2.4-lutidine I i Hydrogen fluoride VI XVII OH |---CH.

CrO; o AceticAcld XVHI patent application, Serial No. 513,901, filed June 7, 1955, by David H. Gould and Hershel L. Herzog.

l,4,6-pregnatriene-17u,21-diol-3,11,20-trione is treated as in Example 1. The residue is the crude 1,4,6-androstatriene-3,11,17-trione and is crystallized from acetone-hexane, M.P. 215 C. (dec.).

EXAMPLE 3 1,4,6-andr0statriene-11B,] 7 fi-diol-3-0ne A culture of Saccharomyces cerevisiae (A.T.C.C. 4125) is grown for 48 hours on an agar medium of the following composition: yeast extract (Difco), 10 g.; cerelose, 60 g.; potassium dihydrogen phosphate, 4.49 g.; disodium hydrogen phosphate, 8.83 g.; agar, 20 g.; and tap water to make 1 liter. The cell material from'one agar slant is suspended in 5 ml. of saline. One ml. of this suspension is added to 100 ml. of the aforedescribed medium (without agar) in a 300 ml. Erlenmeyer flask. The resulting mixture is incubated at 30" on a shaker for 24 hours.

A fermenter containing '2 liters of the agar-free medium is inoculated with the 100 ml. of incubated mixture prepared previously, and is then aerated at a rate of one and one-half volumes of air per volume of medium per minute. After 6 hours of growth, 2 g. of the product of Example 1 in 50 ml. of ethanol is added to the fermenter and the reaction is allowed to proceed for 96 hours. The pH of the broth is then adjusted to 3.5 with dilute hydrochloric acid, and the reaction mixture extracted thoroughly with chloroform. The chloroform extracts are concentrated, the resulting oily residue is taken up in hexane, and extracted three times with aqueous ethanol. The combined ethanol extracts are concentrated to the crude, substance 1,4,6-androstatriene-llfl, 17B-diol-3-one which is then purified by crystallization from acetone-hexane.

EXAMPLE 4 1,4,6-andr0statriene-17fl-0l-3,11-di0ne The requisite intermediate 1,4,6-androstat1iene-3,11,17- trione, prepared as in Example 2, is subjected to the action of a culture of Saccharamyces cerevisiae in the manner outlined in Example 3 to obtain 1,4,6-androstatriene- 17,8-ol-3,11-dione.

EXAMPLE 5 1 7 methyl-1,4,6androstatriene-115,17,6-diol-3-one (A) S-pyrrolidino 3,5 -andr0stadiene-1 1 B-ol-I 7-0ne. A sample of 5 g. of 4-androsten-11p-ol-3,17-dione is suspended in 20 m1. of methanol and nitrogen is passed through to displace air. The mixture is heated to reflux and methanol is added dropwise to complete solution. To

the boiling solution is added 1.8 g. of pyrrolidine and the solution is boiled until crystals appear (about 5 min) The mixture is chilled and filtered, and the solid, 3-pyr-v rolidino-3,S-androstadiene-llfl-ol 17-one, is washed with cold methanol and dried in vacuo.

(B) 1 7-m'ethyl-4-androstene-1-1l8,17fi-diol-3-0ne.--A solution of 1 g. of the pyrrolidine androstadiene prepared as above in 50 ml. of anhydrous dioxane istreated .dropwise with a solution of 0.51 g. of methyl magnesium iodide in 5 ml. of anhydrous ether under a nitrogen atmosphere and anhydrous conditions. After the addition is complete, the mixture is refluxed gently for /2. hour, then treated cautiously with 1 ml. of water. The mixture is filtered. The filtrate is concentrated in-vacuo to 5 ml. and diluted with 50 ml. of 5% acetic acid containing 0.5 g. of sodium acetate. The reaction mixture is, heated on a steam bath for 30. minutes. The precipitate, 1.7-methyl- 4-androstene-115,17,9-diol-3-one, is collected and crystallized from acetone-hexane.

(C) 1 7-met/1yl-1,4-androstadiene-115,1 7B-di0l-3-one. Bacillus splzaericus var. fusiformis (A.T.C.C. 7055) is incubated on nutrient agar for 24 hours at 28 C. One loopful of the culture is then transferred to 100 ml. of sterile 1% yeast extract (Basamin-Busch) of pH 6.8. The inoculated culture is incubated on a shaking machine for 6 hours at 28 C. and the resultant broth culture is used as a standard inoculum at a level of 1%.

The standard inoculum is added to each of ten 300 ml. shake flasks containing respectively 100 ml. of 1% yeast extract at pH 6.8. Growth of the organism is followed turbidimetrically and the product of procedure B (50 mg. in 1 ml. of methanol/flask) is added at the peak of the growth curve. The transformation proceeds rapidly and is followed adequately by paper chromatography or polarography of aliquots from the shake flasks. When the substrate is completely transformed (12-24 hours), the contents of the remaining flasks are pooled, extracted exhaustively with chloroform, and the extracts are concentrated to a residue. The residual material is recrystallized from acetonehexane to give pure 17-methyl-1,4- androstadiene-115,17,8-diol-3-one. I

(D) 17-methyl-1,4 androstadien'e 11 8,] 7B-di0l-3-0ne 11,17-diacetate.-To a solution of 5 g. of the androstadiene-diol of procedure C in 50 ml. of acetic anhydride and 50 ml. of glacial acetic acid is added 0.5 g. of p-toluenesulfonic acid. The reaction mixture is allowed to stand at room temperature overnight and is then treated with water. The resulting precipitate is removed by filtration, chromatographed on magnesium silicate eluting with 1:1 etherhexane, and crystallized from ether-hexane yielding pure 17 methyl 1,4 androstadiene 11,13,17p3-diol-3-one 11,17-diacetate.

(E) 6 bromo 17 methyl-1,4-andrstadiene-11,3,17,3- di0l-3-0ne 11,17-dz'acerate.2 grams of the diacetate preparedin procedure D are dissolved by boiling in 100 ml. of chlorobenzene and 50 ml. of carbontetrachloride. The solution is dried by distilling ml. of the solvent, then 1.88 g. of-N-bromo-succinimide is added.

The mixture is irradiated with a ZOO-Watt photoflood lamp while refluxing for 15 minutes during which time succinimide crystallizes out. After cooling the mixture, the succinimide is filtered, Washed with carbontetrachloride, and discarded. The organic solution is washed with water, dried, filtered, and evaporated in vacuo to a residue which is the 6-bromo-17-methyl-1,4-androstadiene- 1119,176-diol-3-0ne 11,17-diacetate.

(F) 17-methyl-1,4,6-andr0statriene-115,17B-diol-3-0Ize 11,17-diacetwte.-To 151ml, of refluxing dry collidine is added 0.5 g. of the 6-bromo-androstadiene of procedure B. After 30 minutes boiling during which solid precipitates, the mixture is cooled, poured into ice and water and the pH adjusted to 4-6 with dilute hydrochloric acid. The mixture is extracted three times with 25 ml. of meth ylene chloride, and the solution is washed with Water, dried, filtered, and evaporated to dryness.

The residue is dissolved in a minimum of methylene chloride and chromatographed on activated magnesium silicate using hexane to develop the column. The fraction eluted with ether is crystallized further from etherhexane, to give the pure l7- methyl-1,4,6-androstatriene- 11/3,17 8.-diol-3-one 11,17-diacetate.

(G) 17-methyl 1,4,6 androstatrienc 1113,17fi-di0l-3- one.A mixture is prepared of 1 g. of yeast extract concentrate and 1 ml. each of 2 M potassium dihydrogen phosphate and 2 M disodium phosphate in each 100 ml. Ten Erlenmeyer flasks (300 ml.) containing 100 ml. each are sterilized and inoculated with Flavobacterium dehydrogenans var. hydrolyticum. The flasks are shaken at 30 for 16 hours, and to each is added a solution of 50 mg. of the androstatriene diacetate of procedure F in 5 ml. of methanol. The cultures are shaken at 30 for 24 hours and the combined broths are extracted three times with 300 ml. of methylene chloride and the extract is dried, filtered and evaporated to dryness. The residue is crystallized from acetone-hexane to give pure 17-methyl-1,4,6-androstatriene-11fi,17p-diol-3-one which is the desired compound of Example 5.

EXAMPLE 6 17-methyl-1,4,6-andr0statriene-17 3-0l-3,1I-dione Two grams of l7-methyl-1,4,6-androstatriene-l15,175- diol-3-one is dissolved in 20 ml. of pyridine and added with stirring to a cooled slurry of 1 g. of chromic anhydride in 20 ml. of pyridine. The mixture is stirred overnight at room temperature, and then diluted with 40 ml. of 10% aqueous sodium sulfite, followed by stirring for 2 hours. The mixture is acidified with aqueous sulfuric acid and extracted with methylene chloride. This solution is washed neutral with Water, dried, filtered and evaporated to a residue which is crude l7-methyl-1,4,6- androstatriene-17fi-ol-3,1l-dione. The pure product is obtained by crystallization of this residue from acetonehexane.

Alternatively, the compound of this example may be prepared as follows:

(A) 3 pyrrolidino 3,5 androstadiene --11,I7- di0l1e.-When 4-androstene-3,11,17-trione is reacted with pyrrolidine in the manner described in Example 5, procedure A, the compound 3-pyrrolidino 3,S-androstadiene- 11,17-dione is obtained.

(B) 17 methyl 4 -andr0stene 17/3 ol 3,11- di0ne.1 gram of the pyrrolidino androstadiene prepared. as above is treated in the manner described in Example 5, procedure B. Crystallization of the crude precipitate from aqueous acetone yields the pure 17-methyl- 4-androstene-17fi-ol-3,1l-dione.

(C) 17 methyl 1,4 androstadiene 1713 ol 3,11- di0ne.-The androstene compound of above procedure B is subjected to the action of a culture of Bacillus sphaericus in the manner described in Example 5, procedure C. The residue is crystallized from acetone to give 17-methyl-1,47androstadiene-175:01-3,1l dione.

(D) 6 bromo 17 methyl 1,4 androstadiene 17B- al-3,11-di0ne.The product of procedure C is brominated with N-bromosuccinimide as described in Example 5 procedure E. The residue is 6-bromo-17-methyl-l,4-a.ndrostadiene-17fl-ol-3,1l-dione.

(E) 17 methyl 1,4,6 androstatriene 176 ol- 3,11-di0ne.The 6-bromo product of above procedure D is dehydrobrominated with -collidine in the manner described in Example 5, procedure F. The fraction eluated with ether is crystallized further from ether-hexane to give pure 17 methyl 1,4,6 androstatriene 17,8 ol- 3,1l-dione.

EXAMPLE 7 The requisite intermediate, fluoro 1,4,6 pregnatriene-llfl,17a,21-triol-3,20-dione is prepared as described in copending patent application, Serial No. 513,-

901, filed on June 7, 1955, by David H. Gould and Hershel L. Herzog. A

As described in Example 1, 9a-fiuoro-l,4,6-pregnatriene-l1B,17a,2l-triol is treated with sodium bismuthate and the residue is crystallized from methylene chloride-hexane to give 9a-fluoro-1,4,6-androstatriene- 1113-01-3 l7-dione.

EXAMPLE 8 The requisite intermediate, 90: fluoro 1,4,6 pregnatriene-l7a,21-diol-3,l1,20-trione, is prepared as described in copending patent application, Serial No. 513,- 901, filed on June 7, 1955, by David H. Gould and Hershel L. Herzog.

9a fluoro 1,4,6 pregnatriene 17a,21 -diol 3,11,20- trione is treated as in Example 1 to give a residue which is recrystallized from methylene chloride-hexane to give 9u-fluoro-1,4,6-androstatriene-3,11,17-trione.

EXAMPLE 9 9a-fluoro-I,4,6-androstatriene-11B-17fl-diol-3-0ne The produce of Example 7 is subjected to the action of a culture of Saccharomyces cerevisae in the manner described in Example 3 to yield 9u-fluoro-1,4,6-androstatriene-l1,8,17fi-diol-3-one which is purified by recrystallization from acetone-hexane.

EXAMPLE 10 9a-flu0r0-1 ,4,6-andrstatriene-1 7,8-0l-3,11-di0ne The product of Example 8 is subjected to the action of a culture of Saccharomyces cerevisae as described in Ex ample 3 to yield 9a-fiuoro-1,4,6-androstatriene-17 8-01- 3,11-dione.

EXAMPLE l1 (A) 17 methyl 1,4,9(11) androstatriene 1718 ol- 3-0ne.-A sample of grams of 17-methyl-1,4-androstatriene-l1{3,17fi-diol-3-one, prepared as in Example 5, procedure C, is dissolved in 20 ml. of dimethylformamide and 4 ml. of dry pyridine. The solution is chilled and stirred, and 4.1 g. of methane sulfonyl chloride in 41 ml. of dimethylformamide is added.

After being stirred at room temperature for 20 hours, the mixture is poured into 200 ml. of water, and extracted twice with 100 ml. of methylene chloride. The organic layer is Washed with sodium bicarbonate and with water, dried and evaporated. The residue is crystallized from aqueous acetone to give 17-methyl-1,4,9(11)-androstatriene 17 8 ol 3 one, A max=238 m (B) 9a bromo 17 methyl 1,4 androstadiene- 11B,17B-di0l-3-0ne.A sample of 2.5 g. of the product of Example 11, procedure A is dissolved in 250 ml. of dry tetrahydrofuran and 25 ml. of water. The solution is chilled with stirring to 5 and 2.5 g. of N-bromoacetamide is added. After the addition of 25 ml. of 1 N perchloric acid, the mixture is allowed to stand at room temperature for 48 hours.

The solution is diluted with 10% sodium sulfite and water and extracted with 200 ml. of chloroform twice. The extract is washed with water, dried, and evaporated to give a residue which is dissolved in acetone, treated with charcoal, filtered and diluted with hexane. The resulting precipitate is filtered and recrystallized from acetone-hexane, to give 9a-bromo-17-methyl-1,4-androsta diene-l15,175-diol-3-one, A max=242 my.

(C) 17 methyl 93,115 oxido 1,4 -andr0stadiene- 17fi-0l-3-0ne.A sample of 2 g. of the product of Example 11, procedure B is dissolved in 200 ml. of acetone and 4 g. of potassium acetate is added. The solution is refluxed for 24 hours and evaporated to a residue in vacuo. Crystallization from acetone-hexane gives 17- 10 methyl 9 8,113 oxido 1,4 androstadiene 17/8 ol- 3-one,A max=249 mu. v

(D) 6-brom0 -17-me!hyl-9B,1]fi-bxido 1,4 androstadiene-l 7l3-0l-3 1on'e.- A sample of 2 g. of the product of example 11, procedure C'is dissolved by boiling in 100 ml. of chlorobenzene and 50 ml. of carbon tetrachloride, and the solution is dried by distilling 01f 5 ml. of solvent. To the solution is added 1.19 g. of N-bromosuccinimide and the mixture is irradiatedwith-a 200-watt photoflood lamp and refluxed for 15 minutes while succinimide crystallizes out. The mixture is cooled, filtered, and the filtrate is washed with water. The organic solution is dried over Na SO filtered, and evaporated in vacuo to a residue of 6-bromo-17-methyl-9;3,1lfl-oxido-1,4-androstadiene 17B- ol-3-one.

(E) 17-methyl-9;3,11fl-0xid0-1,4,6-androstatriene 17B- 0l-3-0ne.-The product of Example 11, procedure D (1.0 g.) is treated as Example 5, procedure F using 30 ml. of 2,4-lutidine in place of 'y-collidine. Chromatography and elution with ether gives the desired 17-methy1-9B,11;8- oxido-1,4,6-androstatriene-1713-01-3 one, recrystallizable from acetone-hexane, A max=222, 258, 298 m (F) Qa-fluoro-I7-methyl-1,4,6-andr0stene-11,8,17B-diol- 3-0ne.A sample of 1 g. of the product of Example 11, procedure E is dissolved in 100 ml. of anhydrous, alcoholfree chloroform and chilled to 60 in a Dry Ice-acetone bath. The stirred solution is treated with 1 g. of anhydrous hydrogen fluoride for 15 hours when the solution is washed with sodium bicarbonate solution, dried, filtered and evaporated. The residue is chromatographed on activated magnesium silicate and the fraction eluted with ether is crystallized from acetone-hexane to give the desired product, A max at 222, 255 and 296 mu.

In the same manner, use of hydrogen chloride and hydrogen bromide in place of hydrogen fluoride, leads to 9a-chloro and 9oi-bromo-l7methyl-1,4,6-androstatriene- 115,17fi-dio1-3-one, respectively.

EXAMPLE 12 c- Moro-17-methyl-1,4,6-androstatriene-17fi-0l- 3,11-di0ne wherein X is a member of the group consisting of hydrogen and fluorine; Y is a member of the group consisting of and =0; and Z is a member of the group consisting of :0

2. 1,4,6-androstatriene-11,8-ol-3,17-dione. 

1. STEROID COMPOUDS HAVING THE FOLLOWING FORMULA: 